2-acylimino-1,3-diazacycloalkanes

ABSTRACT

1-R1-2-trimethoxybenzoylimino-1,3-diazacycloalkanes, e.g. those of the formula   R1 aliphatic or cycloaliphatic radical R3 H, alkyl or alkanoyl N 2-4 OR SALTS THEREOF EXHIBIT HYPNOTIC EFFECTS.

United States Patent Lucas et al. 1 March 6, 1973 2-ACYLIMlNO-l,3- [56] References Cited DIAZACYCLOALKANES UNITED STATES PATENTS [75] inventors: when A'm'stead Lugs Mendharf; 1,860,036 5 1932 Kranzlgin et al ..260/256.4 11 Herbert summlt 3,121,645 2/1964 Blndlfil el al. ..260/256.4 11 both of Ni 3,627,889 12/1971 Lucas et al. ..424/200 Assigneez Ciba-Geigy C p y 3,655,895 4/1972 Lucas et al. ..424/25l Primary Examiner-Alex Mazel [22] Filed: April 7, 1970 Assistant Examiner-R. J. Gallagher Attorney-Harry Goldsmith, Joseph G. Kolodny and [21] Appl. No.: 26,433 Mario A Monaco Related U.S. Appllcatlon Data 57] ABSTRACT [63] Continuation-impart of Ser. No. 884,322, Dec. 11,

1969, Pat. NO. 3,627,889, which is a continuation-in- 1 :2; dlazacycloal part of Ser. No. 839,704, July 7, 1969, Pat. No. 7 V W 3,655,895. --ocm 0112),. C=Nc0 oc m [52] U.S. Cl....260/256.4 H, 260/239 BC, 260/309], Z --OCHa 424/251, 424/273 [5 l Int. Cl.....C07d 51/18, C07Cl 49/30, C07d 53/02 R aliphatic or cycloaliphatic radical [58] Field of Search ..260/256.4 H, 309.7, 239 BC R H, alkyl or alkanoyl r1 2-4 or salts thereof exhibit hypnotic effects.

3 Claims, No Drawings 2-ACYLIMINO-l ,3-DIAZACYCLOALKANES CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of application Ser. No. 884,322, filed Dec. 11, 1969 (now U.S. Pat. No. 3,627,889 issued Dec. 14, 1971), which in turn is a continuation-in-part of application Ser. No. 839,704, filed July 7, 1969 (now U.S. Pat. No. 3,655,895 issued April II, 1972).

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 5 to 7 ring-membered l-R -2- trimethoxybenzoylimino-l,3-diazacycloalkanes (or of the tautomeric l-R 2-trimethoxybenzoylamino-1,3- diazacycloalkenes or of the isomeric 1-R -2-imino-3- trimethoxybenzoyl-l ,3-diazacycloalkanes) or of N- alkyl or acyl derivatives or salts thereof, wherein R is an unsubstituted or substituted aliphatic or cycloaliphatic radical, preferably of those corresponding to Formula I in which R is lower alkyl, alkenyl or alkynyl, (hydroxy,

lower alkoxy or di-lower alkylamino)-lower alkyl wherein the oxygen or nitrogen atom is separated from the ring-nitrogen atom by at least two carbon atoms, three to seven ring-membered cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl, R, is trimethoxybenzoyl, R is hydrogen, lower alkyl, alkanoyl or aralkanoyl and alk is lower alkylene separating the adjacent nitrogen atoms by two to four carbon atoms, or of salts thereof, as well as of corresponding pharmaceutical compositions and of methods for the preparation and application of these products. Said compositions are useful sedative-hypnotic agents.

DESCRIPTION OF THE PREFERRED EMBODIMENT The substituent R represents preferably lower alkyl, lower alkenyl, lower alkynyl or said (hydroxy, lower alkoxy or dilower alkylamino)-lower alkyl radicals, e.g.,

methyl, ethyl, nor i-propyl or -butyl, 3-methylbutyl, lor 2-pentyl, -hexyl or -heptyl; allyl, methallyl, 2-butenyl, 2-but-2-enyl, 2- or 3-pentenyl, 2-pent-2-enyl or 2- hexenyl; propargyl, 2-butynyl or 2-hex-3-ynyl; 2- (hydroxy, methoxy, ethoxy, dimethylamino, diethylamino, di-n or i-propylamino)-ethyl or -propyl, 3-(hydroxy, methoxy or dimethylamino)-propyl or -butyl; but also three to seven ring-membered cycloalkyl,

0 cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyllower alkyl radicals, e.g., cyclopropyl, cyclopentyl or cyclohexyl; lor 2-cyclopentenyl, -cyclohexenyl or cycloheptenyl; cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl or cyclohexylmethyl; l-cyclopentenylmethyl, 2-cyclopent-1-enylethyl or l-cyclohexenylmethyl, The term "lower referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to seven, preferably up to four, carbon atoms.

The trimethoxybenzoyl radical R contains the methoxy groups in any of the 5 positions of the phenyl nucleus thereof. It preferably represents 3,4,5- trimethoxybenzoyl, but also, for example, 2,3,4- or 2,4,5-trimethoxybenzoyl.

Acyl derivatives of the invention are derived from aliphatic or aromatic carboxylic acids, preferably of lower alkanoic or aralkanoic acids. Thus the radical R represents, for example, acetyl, propionyl or pivalyl; benzoyl, mono-, dior trimethoxybenzoyl or phenylacetyl.

The alkylene moiety alk", separating the nitrogen atoms of the 1,3-diazacycloalkane moiety by two-four carbon atoms, preferably represents l,2-ethylene or 1,3-propylene but also, for example, 1,2-propylene, 1,2-, 1,3-, 1,4- or 2,3-butylene, l,2-, l,3-, I,4-, 2,3- or 2,4-pentylene, -hexylene or -heptylene.

The compounds of the invention exhibit valuable pharmacological properties. Besides central nervous system depressing effects, such as sedative and skeletal muscle relaxing effects, they predominantly exhibit hypnotic effects. This can be demonstrated in animal tests, using advantageously mammals, such as mice, rats, rabbits, cats, dogs or monkeys as test objects. The compound of the invention can be applied to the animals enterally or parenterally, e.g., orally, intraperitoneally or intravenously, for example, in gelatin capsules or in the form of aqueous solutions or suspensions. The oral dosage may range in the lower animals, e.g., mice or rats, between about 1 and about 500 mg/kg/day, preferably between about 5 and about 200 mg/kg/day, and in the higher animals, e.g., dogs or monkeys, advantageously between about 10 and about 50 mg/kg/day. The effect on the spontaneous and induced motor activity is observed in the mice jiggle cage, light box or rotorod test systems, wherein a depression is recorded after oral medication. Oral doses in the cat induce a sleep-like state (constricted pupils and relaxed nictitating membrances) from which the animal can be aroused without showing motor incoordination. Oral doses produce also sleep in dogs and monkeys, wherein the animals assume a normal position. Low nitravenous doses produce in the cat depression. of several reflexes, e.g., the flexor and patellar reflex, and in the rabbit a lesser reduction of the respiratory rate as with conventional hypnotics at equihypnotic doses. Accordingly, the compounds of the in vention are useful sedative-hypnotic agents, for example, in the treatment or management of restlessness and emotional tension, for suppression of anxiety and neurotic manifestations, and preferably for the induction of sleep. They are also useful intermediates in the preparation of other valuable products, especially of pharm acologically active compounds.

Particularly useful are the compounds of Formula I, in which R is alkyl with up to four carbon atoms, R is 3,4,5-trimethoxybenzoyl, R is hydrogen or alkyl with up to four carbon atoms and alk is 1,2-ethylene, 1,2- or 1,3-propylene, as well as those compounds of Formula I, in which R is also alkenyl or alkynyl with up to four carbon atoms, R is also alkanoyl with up to four carbon atoms and alk is also 1,2-, 1,3-, 1,4- or 2,3-butylene, as well as those compounds of Formula I, in which R is also (hydroxy, alkoxy or dialkylamino)- alkyl wherein alkyl contains up to four carbon atoms and the oxygen or nitrogen atom therein is separated from the ring-nitrogen atom by at least 2 carbon atoms and R is also 2,3,4- or 2,4,5-trimethoxybenzoyl, or therapeutically acceptable acid addition salts of all these compounds.

in which R is methyl, ethyl, n-propyl, allyl or 2- dimethylaminoethyl, R is hydrogen, methyl or acetyl and n is an integer from 2 to 4, preferably 3, more particularly the l-methyl-2-( 3 ,4, 5 -trimethoxybenzoylimino)-hexahydropyrimidine, or therapeutically acceptable acid addition salts thereof, which exhibit a high order of sedative-hypnotic activity and low toxicity, preferably after oral application.

The compounds of this invention are prepared according to methods known per se. For example, the process for their preparation consists in:

a. acylating a l-R,-2-imino-3-R -l,3-diazacycloalkane with a tri-methoxybenzoic acid or a reactive functional derivative thereof or i b. converting in an N-Y-trimethoxybenzamide or imide, in which Y is a substituent convertible into a l-R,-3-R -1,3-diazacyclo-2-(alkenyl or alkylidene) radical respectively, Y into said radical or c. methylating a l-R,-3-R -2-trihydroxybenzoylimino-l ,3-diazacyclo-alkane or d. hydrogenating a l-R,-2-R,-imino-3-R -l,3-diazacycloalkene or -alkadiene and, if desired, converting any resulting 5 to 7 ring-membered compound into another compound of the invention.

The acylation according to item (a) is advantageously performed with a reactive functional derivative of the trimethoxybenzoic acid, such as a lower alkyl ester, halide, e.g., chloride or bromide, or anhydride thereof, e.g., the simple or a mixed anhydride with any other suitable acid, such as a loweralkyl carbonic acid.

In the starting material mentioned under item (b), the substituent Y is, for example, a l-unsubstituted 3- R -l,3-diazacyclo-2-(alkenyl or alkylidene) radical, which can be substituted in the 1-position, for example, by reaction with a reactive ester of the alcohol R,-

OH, for example, that of a strong mineral or sulfonic acid, such as a hydrohalic acid, e.g., hydrochloric, hydrobromic or hydroidic acid, sulfuric acid or a lower alkane or benzene sulfonic acid, e.g., methane-, ethaneor p-toluenesulfonic acid. Another substituent Y is, for example, a cyano or dialkylmercaptomethylene group, e.g., dimethylmercaptomethylene, or a thiocarbamoyl or S-alkyl-isothiocarbamoyl group or the N'-R or N-R derivatives thereof. The corresponding starting material, i.e., an N-R -cyanamide, a dialkyl N-R -dithiocarbaminate, N-R -thiourea, N,N- bis-R -thiourea or advantageously an S-aIkyI-N-R isothiourea or S-alkyl-N,N-bis-R -isothiourea respectively, is condensed with the diamine R -NH-alk-NH- R wherein R is hydrogen or loweralkyl, in order to obtain the compounds of the invention.

The methylation according to item (c) is advantageously performed with diazomethane, but also with a reactive ester of methanol, e.g., such mentioned above for R,OI-I.

The hydrogenation according to item (d) is preferably carried out with catalytically activated or nascent hydrogen, for example hydrogen applied in the presence of nickel, platinum or palladium catalysts or generated electrolytically or by the action of metals on acids or alcohols, such as heavy metals, e.g., zinc or iron, on mineral or carboxylic acids, or light metals, e.g., sodium or-magnesium, on alkanols.

The compounds of the invention so obtained, can be converted into each other according to methods known per se. For example, resulting compounds of Formula I in which R is hydrogen, can be acylated or alkylated in 3-position as shown under items a) and b), i.e., with reactive functional derivatives of aliphatic or aromatic acids or reactive esters of lower alkanols respectively. Resulting compounds in which R is an acyl group, e.g., trimethoxybenzoyl or lower alkanoyl, can be hydrolyzed, e.g., by the careful application of acidic or alkanline hydrolyzing agents, such as aqueous mineral acids or alkalis, e.g., hydrohalic or sulfuric acids, or alkali metal, e.g., sodium or potassium, hydroxides, carbonates or bicarbonates.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the above process is carried out. A resulting free base can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, preferably a therapeutically useful acid, or with a corresponding anion exchange preparation, and isolating the desired slat. An acid addition salt may be converted into the free compound by treatment with a base, e.g., a metal hydroxide, ammonia or a hydroxyl ion exchange preparation. Therapeutically useful acids are, for example, inorganic acids, such as strong metalloidic acids, for example, hydrohalic, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as carboxylic or sulfonic acids, e.g., formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4- aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicyclic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic,

naphthalenesulfonic, sulfanilic and cyclohexylsulfamic acid; methionine, tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used for purification of the resulting free compounds, which are converted into salts, the salts separated and the free compounds liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g., by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g., by the fractional crystallization of dor l-tartrates.

The above reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing, neutralizing agents and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure. For example, in the above acylation or alkylation reactions, the generated mineral or sulfonic acid may be neutralized with inorganic or organic bases, such as alkali or alkaline earth metal carbonates or bicarbonates, tri-lower alkylamines or pyridine.

The invention also comprises any modification of the above process, wherein a compound resulting as an intermediate at any stage thereof, is used as starting material and the remaining steps are carried out or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salts or reactive derivatives. For example, in the reaction according to item (b) with compounds in which Y is dialkylmercaptomethylene, the intermediate formed first is an S- alkyl-N-R -isothiourea, which ring0closes in a second step under the influence of heat and/or acidic catalysts. Also in the methylation reaction according to item (c), dihydroxymethoxyand dimethoxy-hydroxybenzoylimino intermediates are formed during the etherification procedure which, of course, can also be chosen as starting materials. The hydrogenation according to item (d) may also be carried out stepwise, for example, a l-R -2-R,-imino-l,3-diazacycloalkadiene can first be reduced with sodium borohydride to the corresponding l-R -2-R imino-3H-l,3-diazacycloalkene, with latter or its 3-R -derivative, is subjected to hydrogenation. Preferred are starting materials, which lead to those compounds of the invention, which are indicated above as the preferred embodiments of the invention.

The starting materials used are known or, if new, may be prepared according to the methods illustrated in the examples herein. For example, the starting material mentioned under item a) is prepared in accordance with the methods described in US. Pat. No. 3,027,370 or British Pat. No. 765,547. The starting material mentioned under item (b) in which Y is a lunsubstituted 3-R -l,3-diazacyclo-2-(alkenyl or alkylidene) radical, can be obtained either by the acylation method according to item (a) or from corresponding 1- benzyl-2-R -3-R -l,3-diazacycloalkanes, which are subjected to reductive cleavage, e.g., with the use of catalytically activated hydrogen. The starting material, in which Y is advantageously bis-(lower alkylmercapto)-methylene, can be obtained by addition of lower alkylmercaptanes to trimethoxybenzoylisothiocyanates and reacting the resulting dithiourethanes with a lower alkyl halide or sulfonate. The thioureas or isothioureas also mentioned under item (b) as well as the starting material mentioned under items (c) and (d) can be prepared analogous to the acylation process described under item (a), i.e., by reacting the corresponding benzoic acid derivatives, advantageously their lower alkyl esters or halides, with the respective nitrogen bases. The starting material mentioned under items (c) and (d) as well as the process intermediates thereof, e.g., the l-R -3-R -2-(methoxy-dihydroxy-or hydroxydimethoxy-benzoylimino)-l,3-diazacycloalkanes, are new and are considered as additional subject matter of the present invention. They also exhibit central nervous system depressing effects similar to those observed with the compounds of Formulas I or ll. Preferred are the compounds mentioned under item (d) which yield the products of Formula ll, i.e., those corresponding to Formulas III and IV wherein each or p and q is an integer from 0 to 2 and p q is not greater than 2, Z is either nitrogen or the moiety Cl-l-N-R and R, is 3,4,5-trimethoxybenzoyl, or acid addition salts thereof.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or e) adsorbents, colorants, flavors and sweeteners. lnjectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions, They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to percent,

preferably about 1 to 50 percent of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 To the solution obtained from 5.76 g sodium and 100 ml anhydrous methanol, 48.58 g l-methyl-2-imino-hexahydropyrimidine hydrobromide are added while stirring and cooling. After one-half hour, the mixture is evaporated in vacuo on the water bath for 4 hours. Hereupon 125 ml tetrahydrofuran are added under nitrogen followed by the solution of 28.8 g 3,4,5- trimethoxybenzoyl chloride in 185 ml tetrahydrofuran during 35 minutes at 5 1 while stirring. After stirring overnight at room temperature, the mixture is poured onto 770 ml ice and water and 21.2 g sodium bicarbonate are added while stirring. The mixture is extracted three times with 100 ml methylene chloride, the extract dried, filtered and evaporated below 40. The residue is triturated with 45 ml diethyl ether for 1 hour at room temperature, the mixture filtered and the residue washed with cold diethyl ether, to yield the 1- methyl-2-(3,4,5-trimethoxybenzoylimino )-hexahydropyrimidine of the formula meltin 51 142 1 6 7 The starting material is prepared as follows: To the mixture of 97.6 g 3-methylamino-propylamine and 270 ml methanol, the solution of 118 g cyanogen bromide in 170 ml methanol is added dropwise during 2 hours at l5 while stirring. After stirring at room temperature overnight, the mixture is refluxed for 6 hours and evaporated in vacuo. The residue is recrystallized from 217 ml hot isopropanol and dried for 5 hours in vacuo,

to yield the 1-methyl-2-imino-hexahydropyrimidine hydrobromide melting at 142144.

EXAMPLE 2 To the solution obtained from 2.3 g sodium and 40 ml methanol, 19.4 g 1-methyl-2-imino-hexahydropyrimidine hydrobromide are added portionwise while stirring. After the initial lumps formed are dissolved, the mixture is evaporated in vacuo at room temperature for about 3 hours. The dry residue is slurried in 40 ml tetrahydrofuran and 30 ml triethylamine, whereupon the solution of 23 g 3,4,5-trimethoxybenzoyl chloride in ml tetrahydrofuran is added during 15 minutes at 5-l5 while stirring. The mixture is stirred at room temperature overnight and evaporated in vacuo. The residue is shaken with 60 ml methylene chloride and 60 ml aqueous ammonia, and the aqueous phase washed with methylene chloride. The combined organic solution is washed with 30 ml water, dried, filtered and evaporated in vacuo. The residue is taken up in 60 ml benzene and the solution extracted with 30 ml water and 30 ml 10 percent hydrochloric acid. The combined aqueous layer is made basic with ammonia, the precipitate formed fil tered off, washed with water, dried and recrystallized from tetrahydrofuran, to yield the l-methyl2-(3,4,5- trimethoxybenzoylimin0)-3-(3,4,5-trimethoxybenzoyl)-hexahydropyrimidine of the formula Preparation of 1,000 tablets each containing 250 mg of the active ingredient:

Formula: l-methyl-2-( 3 ,4,5-trimethoxybenzoylimino)-hexahydropyrimidine 250.0 g Wheat starch 346.8 g Magnesium aluminum silicate 20.0 g Methylcellulose 13.3 g Stearic acid 133 g Colloidal silica 6.6 g Anhydrous ethanol q.s. Purified water q.s.

Procedure:

All powders with the exception of the silica and 96.8 g of the starch are passed through a screen having openings of 0.6 mm and mixed well. From the remaining starch and ml water a paste is formed which is used to granulate the powders together with the ethanol. The wet granulate is passed through a screen with 2 mm openings and dried overnight at 35. The dry granulate is broken in a hammer mill, passed through a screen with 1.2 mm openings and compressed into tablets each weighing 0.65 g, using concave punches with 12 mm diameter, uppers quartered.

EXAMPLE 4 To the solution of 1 g 1-methyl-2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine in 5 ml pyridine, 1 ml acetic anhydride is added and the mixture allowed to stand at room temperature for 2 days. It is evaporated in vacuo, the residue dissolved in 2 ml hot tetrahydrofuran and the precipitate formed after coo1- ing filtered off, to yield the 1-methyl-3-acetyl-2-(3,4,5- trimethoxybenzoylimino)-hexahydropyrimidine of the formula melting at l35137.

' EXAMPLE 5 To the solution of 5 g 2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine in 50 ml dimethylformamide, 0.7 g of 57 percent sodium hydride in mineral oil are added and the mixture stirred for 1 hour at room temperature. After cooling to 5, the mixture of 1.5 ml ethyl iodide and 12 ml dimethylformamide is added dropwise during 7 minutes and the mixture stirred 3 hours at room temperature. It is diluted with ml ice water, extracted with methylene chloride, the extract dried, filtered and evaporated. The residue is triturated with 15 ml cyclohexane, filtered off and washed with cyclohexane,

to yield the l-ethyl-2-( 3 ,4,5-trimethoxybenzoylimino)-hexahydropyrimidine of the formula 5 melting at l23l 25.

In the analogous manner, the l-n-propyl-2-(3,4,5-tri- V methoxybenzoylimino)-hexahydropyrimidine is prepared, melting at l06l07.

The starting material is prepared as follows: To the solution obtained from 2.3 g sodium and 50 ml methanol, 18 g 2-imino-hexahydropyrimidine hydrobromide are added while stirring and cooling. After one-half hour, 22.6 g methyl 3,4,5-trimethoxybenzoate are added, the mixture stirred one-half hour at room temperature and gradually heated to the internal temperature of about 140-150 while distilling off methanol. Said temperature is maintained for one-half hour and the mixture further evaporated in the vacuum of a water-jet pump. The residue is taken up in 20 ml water, the mixture extracted with 60 ml methylene chloride, the extract dried, filtered and evaporated. The residue is taken up in 30 ml hot benzene, the solution cooled, the crystals formed filtered off, dissolved in 80 ml methanol, the solution concentrated to half the volume, the precipitate formed filtered off and washed with methanol, to yield the 2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine melting at l81-l83. From the combined mother liquors another crop thereof can be obtained.

By replacing the 18 g 2-imino-hexahydropyrimidine hydrobromide by 19.4 g of its l-methyl derivative, and following the procedure given, the compound of Example l is obtained.

EXAMPLE 6 To the solution of 5 g of 2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine in ml dimethylformamide, 0.7 g of 57 percent sodium hydride in mineral oil are added and the mixture stirred for 1 hour at room temperature. After cooling to 5, the mixture of 1.5 ml allyl chloride and 11.5 ml dimethylformamide is added dropwise during 7 minutes and the mixture stirred 3 hours at room temperature. It is diluted with 180 ml ice water, extracted with methylene chloride, the extract dried, filtered and evaporated. The residue is triturated with 15 ml pentane, taken up in the minimum amount of benzene and the solution chromatographed on g aluminum oxide. Two hundred ml of the first benzene eluate are col- 60 lected, evaporated and the residue recrystallized from methanol, to yield the 1-allyl-2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine of the formula melting at l44-l46.

EXAMPLE 7 To the solution of 1 g 2-(3,4,5-trimethoxybenzoylimino)-imidazolidine in 10 ml dimethylformamide, 0.15 g 56.8 percent sodium hydride in mineral oil are added and the mixture stirred for 1 hour. Hereupon 0.25 ml methyl iodide in 2.5 ml dimethylformamide are added dropwise at about 5 while stirring. The mixture is stirred for 3 hours at room temperature and diluted with.36 ml ice water. The precipitate formed is filtered off, washed with water, dried and recrystallized from methanol, to yield the l-methyl-2-(3,4,5-trimethoxybenzoylimino)-imidazolidine of the formula melting at 20l203.

The starting material is prepared as follows: To the mixture of 60.1 g ethylene diamine and ml methanol, the solution of 106 g cyanogen bromide in 100 ml methanol is added dropwise during 90 minutes while stirring and keeping the temperature below 10. The mixture is stirred at room temperature overnight, refluxed for 6 hours and evaporated in vacuo. The residue is recrystallized several times from isopropanol, to-yield the 2-imino-imidazolidine hydrobromide melting at-129.

16.6 g thereof are added to the solution obtained from 2.3 g sodium and 40 ml methanol, and the mixture is stirred for one-half hour at room temperature. Hereupon 22.6 g methyl 3,4,5-trimethoxy-benzoate are added and the mixture stirred for one-half hour at room temperature. It is slowly concentrated, the concentrate stirred at l40-l50 for one-half hour and finally evaporated at 12 mm Hg. The residue is taken up in 60 ml. water, the mixture extracted with methylene chloride, the extract filtered and evaporated. The residue is triturated with 40 ml diethyl ether and recrystallized from methanol, to yield the 2-(3,4,5- trimethoxybenzoylimino)-imidazolidine melting at l49-150.

EXAMPLE 8 To the solution of 1 g l-methyl-2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine in 20 ml dimethylformamide, 0.137 g 56.8 percent sodium hydride in mineral oil are added and the mixture stirred at room temperature for 1 hour. It is cooled to about 5, 0.21 ml methyl iodide in 2 ml dimethylformamide are added dropwise at said temperature and the mixture is stirred for 3 hours at room temperature. It is diluted with 60 ml water and 10 ml saturated aqueous sodium chloride, extracted with methylene chloride, the extract dried, filtered and evaporated. The residue is recrystallized from tetrahydrofuran, to yield the 1,3- dimethyl-2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine of the formula 6k; acii melting at 184l 86.

EXAMPLE 9 To the solution of 0.586 g 2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine in 5.8 ml dimethylformamide, 0.288 g Z-dimethylaminoethyl chloride hydrochloride and 0.256 g potassium hydroxide are added and the mixture stirred at room temperature for 22 hours. It is diluted with 24 ml ice water, extracted with methylene chloride, the extract dried and evaporated. The residue is taken up in diethyl ether, the solution filtered and the filtrate concentrated, to yield the 1-(Z-dimethylaminoethyl)-2-(3,4,5- trimethoxybenzoylimino)-hexahydropyrimidine of the formula EXAMPLE 10 To 2.79 ml dimethylformamide, 0.279 g 2-(3,4,5- trimethoxybenzoylimino)-imidazolidine, 0.144 g 2- dimethylaminoethyl chloride hydrochloride and 0.128 g potassium hydroxide are added in this order while stirring and stirring is continued for 21 hours at room temperature. Hereupon the solution is diluted with 12 ml ice water, extracted with methylene chloride, the extract dried and evaporated. The residue is taken up in 5 ml warm water and the precipitate formed after cooling is filtered off and dried at room temperature, to yield the 1-(Z-dimethylaminoethyl)-2-(3,4,5- trimethoxybenzoylimino)-imidazolidine of the formula arrow- 01191 EXAMPLE 1 1 To the solution of 2.65 g 1-methyl-2-galloyliminohexahydropyrimidine in 30 ml methanol, 33 ml N- ethereal diazomethane are added dropwise while stirring and the mixture is allowed to stand overnight at room temperature. Hereupon a few drops acetic acid are added, the mixture evaporated in vacuo and the residue taken up in 5 percent aqueous sodium carbonate. The mixture is extracted with methylene chloride, the extract dried, filtered, evaporated and the residue is triturated with diethyl ether, to yield the lmethyl-2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine, melting at 142-145; it is identical with the compound obtained according to Example 1.

The starting material is prepared as follows: The mixture of 9.2 g methyl gallate, 20 ml methanol and 5.7 g l-methyl-2-imino-hexahydropyrimidine is slowly concentrated to reach a temperature between l40150. After one-half hour the mixture is evaporated in vacuo, to yield the l-methyl-2-galloylimino-hexahydropyrimidine, which is used as such without further purification.

EXAMPLE 12 0.3 g l-methyl-2-(3,4,5-trimethoxybenzoylimino)- l,2,3,4-tetrahydropyrimidine is hydrogenated in 10 ml ethanol over 0.03 g platinum catalyst at room temperature and atmospheric pressure. After the consumption of the theoretical amount of hydrogen, the mixture is filtered, the filtrate evaporated and the residue recrystallized from isopropanol, to yield the l-methyl- 2-(3,4,5-trimethoxybenzoylimino)-hexahydropyrimidine, melting at l43145; it is identical with the compound obtained according to Example 1.

The starting material is prepared as follows: To the solution of 4.74 g 1-methyl-2-imino-l,2- dihydropyrimidine hydroiodide in 47.4 ml dimethylformamide, 0.845 g percent sodium hydride in mineral oil are added at 15 while stirring. After 1 hour the mixture is cooled to 5 and the solution of 2.3 g 3,4,5- trimethoxybenzoyl chloride in 6.9 ml tetrahydrofuran is added dropwise. After 3 hours stirring at room temperature, ml ice water and 0.7 g potassium carbonate are added, the mixture extracted with methylene chloride, the extract dried, filtered and evaporated. The residue is triturated with 10 ml diethyl ether, filtered off and washed with diethyl ether. The residue is taken up in methylene chloride, the solution extracted with 10 ml 15 percent hydrochloric acid, the aqueous layer made basic with ammonia and extracted with methylene chloride. The extract is dried, evaporated and the residue recrystallized from tetrahydrofuran, to yield the 1-methyl-2-(3,4,5- trimethoxybenzoylimino)-l ,2-dihydropyrimidine of the formula OCH;

EXAMPLE 13 Preparation of 10,000 capsules, each containing 250 mg of the active ingredient:

Fon'nula: 1-al1yl-2-( 3 ,4.5 -trimethoxybenzoylimino)-hexahydropyrimidine 2,500 g Lactose 1,500 g Talcum Powder 300 g Procedure:

in which R is alkyl, alkenyl or alkynyl each with up to four carbon atoms, (hydroxy, alkoxy or di-alkylamino)-alkyl wherein alkyl contains up to four carbon atoms and the oxygen or nitrogen atom is separated from the ring-nitrogen atom by at least two carbon atoms, R, is trihydroxybenzoyl, dihydroxy-m ethoxybenzoyl or di-methoxy-hydroxybenzoyl, R 3 is hydrogen, alkyl or alkanoyl each with up to four carbon atoms and alk is alkylene containing and separating the adjacent nitrogen atoms by two to four carbon atoms.

2. A compound as claimed in claim 1 and having the formula in which R, is trihydroxybenzoyl, dihydroxy-methoxybenzoyl or di-methoxy-hydroxybenzoyl, R is methyl, ethyl, n-propyl, allyl or 2-dimethylaminoethyl, R is hydrogen, methyl or acetyl and n is an integer from 2 to 4.

3. A compound as claimed in claim 1 and being the l-methyl-2-galloylimino-hexahydropyrimidine. 

1. A compound of the formula
 2. A compound as claimed in claim 1 and having the formula 